Konstantinos Lazaridis's long-term research objective is to better understand the pathogenesis of Primary Biliary Cirrhosis (PBC) a chronic, progressive cholestatic liver disease that predisposes to hepatic failure and shortens patients' life expectancy. PBC affects mainly women, clusters in families, and the presence of antimitochondrial antibodies (AMA) is the hallmark of diagnosis. To date, the etiology and pathophysiology of PBC remain frustratingly elusive, which, prevents the development of novel rational therapies. It is generally believed that PBC is caused by immune-mediated damage of bile ducts in a genetically predisposed individual as a reaction to probable environmental insult(s). Yet, the proposed environmental constituent(s) and the putative genetic loci involved in PBC susceptibility and the underlying pathobiology have not been elucidated. In his proposed studies, Dr. Lazaridis takes a genetic epidemiology approach to shed light on the underpinning mechanisms of this enigmatic disease. In the nurturing scientific environment and outstanding research facilities and resources of the Mayo Clinic, the K23 Mentored Patient-Oriented Research Career Development Award would provide Dr. Lazaridis with an excellent opportunity to obtain significant experience in conducting high-quality genetic epidemiology studies in PBC. His proposed studies focus on developing a detailed, research resource of 500 clinic-based, well-phenotyped PBC cases, a family registry of the parents and siblings of the cases, and 500 well-matched, clinic-based controls linked to genomic DNA/cell lines and a serum bio-specimens repository. His HYPOTHESES are: (i) putative environmental and genetic factors predispose to PBC; (ii) PBC and AMA exhibit familial aggregation. He will use the unique research resources to: (i) estimate risk of PBC associated with biologically plausible candidate genes, environmental exposure (smoking) and gene/environment interaction; (ii) compare prevalence of PBC and AMA in parents and siblings of cases compared to controls. This award will provide Dr. Lazaridis with protected research time to generate and test, meaningful scientific data, obtain broad exposure and expertise in genetic epidemiology and statistical genetic analysis. This training and the preliminary results of this study will advance his academic career, prepare him to successfully compete for independent peer-reviewed funding, and develop his own independent research program committed to academic research in cholestatic liver diseases.